Metabolomic and Proteomic Changes Induced by Histamine Antagonist Treatment in a Negative Pulmonary Arterial Hypertension Trial

RATIONALE Pulmonary arterial hypertension (PAH) is a devastating disease with high mortality and morbidity. The significant clinical and molecular heterogeneity of PAH presents challenges in identifying effective therapeutic interventions. Targeting molecular changes through advanced omics profiling may offer new insights into treatment effects. METHODS In an NIH-sponsored, single-center, randomized, placebo-controlled trial of famotidine (an H2 receptor antagonist), 79 adults with PAH received treatment and clinical follow-up over 24 weeks. The primary end-point, 6-minute walk distance at 24 weeks, was not statistically different between the two groups. We collected plasma metabolomic and proteomic profiling on 1118 metabolites and 6386 unique proteins at time of enrollment and 24-week follow-up. Baseline metabolomic and proteomic profiles were compared between treatment arms, and paired analyses were performed to assess the impact of famotidine. Significant metabolites, proteins and pathways were identified, controlling for multiple comparisons. All analyses were adjusted for age, sex, body mass index and PAH etiology. RESULTS Of the 79 participants with PAH, 40 were assigned to in the famotidine arm and 39 to the placebo arm at baseline. No significant differences in metabolomic or proteomic profiles were detected between the two groups at baseline. By the 24-week follow-up, 34 participants remained in the famotidine group and 37 in the placebo group. Although metabolomic changes were not observed, famotidine treatment was associated with significant changes in 704 proteins and 20 proteomic pathways (adjusted p-value < 0.05) (see Figure). CONCLUSIONS This study demonstrates that robust randomization effectively balances clinical and molecular profiles between treatment groups. Our findings show that plasma metabolites and proteins are valuable tools for assessing molecular changes in response to therapy, even in the absence of significant clinical differences. Famotidine treatment induced notable proteomic alterations over the 24-week period, highlighting its potential molecular effects, while metabolomic changes were minimal. These results emphasize the need for future biomarker research to identify subgroups of patients who may have greater molecular responsiveness to famotidine, supporting the development of more personalized therapeutic approaches in PAH management. Figure: Summary plots of the 704 proteins significantly associated with treatment effect of famotidine for participants with pulmonary arterial hypertension. Each line represents the average fold change in protein expression over 6 months for each treatment group, highlighting the differences in response between groups.